Epidemiologic and experimental studies have established that obesity is an important risk and/or prognostic factor for most cancer types, but the mechanisms underlying the obesity-cancer link have not been clearly elucidated. This knowledge gap is hampering efforts to develop mechanism-based strategies to more precisely intervene to prevent and control obesity-related cancers. Given the rising rates of obesity and cancer worldwide, and the challenges for many people to lose excess weight, I propose an integrated multilevel approach to address four critical questions that will lead to new, effective mechanism-based interventions to offset obesity-associated increases in cancer burden: i) Does moderate weight loss alone, or in combination with other mechanism-based interventions, reverse the procancer effects of obesity? ii) What are the mechanisms of (and solutions to) obesity-induced chemotherapeutic resistance? iii) What are the targets and strategies for offsetting the pro-metastatic effects of obesity? iv) What new targets for offsetting the effects o obesity can be identified by deconvoluting (and ultimately disrupting) the reciprocal crosstalk between adipocytes, macrophages and epithelial cells? The overarching goal is to capitalize on our expertise in energy balance and cancer research (including well-characterized preclinical models of breast, colon and pancreatic cancer and well-established collaborations spanning molecular/cellular biologic approaches to clinical trials and epidemiologic studies) to elucidate mechanistic targets, identify new biomarkers that can be used in parallel human and animal studies, and develop effective interventions to break obesity-cancer links and reduce the burden of cancer in obese people.